HMGA1 promotes chemoresistance in esophageal squamous cell carcinoma (ESCC) by suppressing ferroptosis. The study shows that HMGA1 is upregulated in ESCC and enhances cisplatin (DDP) resistance by repressing ferroptosis. Inhibition of HMGA1 increases ESCC sensitivity to ferroptosis. HMGA1 upregulates SLC7A11, a key transporter maintaining intracellular glutathione homeostasis and inhibiting malondialdehyde (MDA) accumulation, thereby suppressing ferroptosis. HMGA1 acts as a chromatin remodeling factor, promoting the binding of activating transcription factor 4 (ATF4) to the SLC7A11 promoter, enhancing its transcription and maintaining redox balance. Depletion of HMGA1 promotes ferroptosis and restores ESCC sensitivity to DDP, enhancing therapeutic efficacy. The study highlights HMGA1 as a critical regulator of ferroptosis in ESCC, suggesting that HMGA1-based strategies could overcome ESCC chemotherapy resistance. The findings were validated using syngeneic allograft tumor models and genetically engineered mice, demonstrating that HMGA1 depletion enhances DDP sensitivity and improves treatment outcomes in ESCC.HMGA1 promotes chemoresistance in esophageal squamous cell carcinoma (ESCC) by suppressing ferroptosis. The study shows that HMGA1 is upregulated in ESCC and enhances cisplatin (DDP) resistance by repressing ferroptosis. Inhibition of HMGA1 increases ESCC sensitivity to ferroptosis. HMGA1 upregulates SLC7A11, a key transporter maintaining intracellular glutathione homeostasis and inhibiting malondialdehyde (MDA) accumulation, thereby suppressing ferroptosis. HMGA1 acts as a chromatin remodeling factor, promoting the binding of activating transcription factor 4 (ATF4) to the SLC7A11 promoter, enhancing its transcription and maintaining redox balance. Depletion of HMGA1 promotes ferroptosis and restores ESCC sensitivity to DDP, enhancing therapeutic efficacy. The study highlights HMGA1 as a critical regulator of ferroptosis in ESCC, suggesting that HMGA1-based strategies could overcome ESCC chemotherapy resistance. The findings were validated using syngeneic allograft tumor models and genetically engineered mice, demonstrating that HMGA1 depletion enhances DDP sensitivity and improves treatment outcomes in ESCC.